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Paraben

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General chemical structure of a paraben
(a para-hydroxybenzoate)
where R = an alkyl group

Parabens are a class of chemicals widely used as preservatives in the cosmetic and pharmaceutical industries. Parabens are effective preservatives in many types of formulas. These compounds, and their salts, are used primarily for their bactericidal and fungicidal properties. They can be found in shampoos, commercial moisturizers, shaving gels, personal lubricants, topical/parenteral pharmaceuticals, spray tanning solution and toothpaste. They are also used as food additives.

Their efficacy as preservatives, in combination with their low cost, the long history of their use, and the inefficacy of natural alternatives like grapefruit seed extract (GSE),[1] probably explains why parabens are so commonplace. They are becoming increasingly controversial, however, because they have been found in high concentrations in breast cancer tumors. [2] Parabens have also displayed the ability to weakly mimic estrogen (a hormone known to play a role in the development of breast cancer).[2] No causal link between parabens and cancer has been established, however.[3]

Chemistry

Parabens are esters of para-hydroxybenzoic acid, from which the name is derived. Common parabens include methylparaben (E number E218), ethylparaben (E214), propylparaben (E216) and butylparaben. Less common parabens include isobutylparaben, isopropylparaben, benzylparaben and their sodium salts. The general chemical structure of a paraben is shown at top right, where R symbolizes an alkyl group such as methyl, ethyl, propyl or butyl.

Occurrence

Some parabens are found naturally in plant sources. For example, methylparaben is found in blueberries,[4][5][6] where it acts as an antimicrobial agent. However, when parabens are eaten, they are metabolised and lose the ester group, making them less strongly estrogen-mimicking.[7]

Synthesis

All commercially used parabens are synthetically produced, although some are identical to those found in nature. They are produced by the esterification of para-hydroxybenzoic acid with the appropriate alcohol. para-Hydroxybenzoic acid is in turn produced industrially from a modification of the Kolbe-Schmitt reaction, using potassium phenoxide and carbon dioxide.

Toxicology

Studies on the acute, subchronic, and chronic effects in rodents indicate that parabens are practically non-toxic.[8][9] Parabens are rapidly absorbed, metabolized, and excreted.[8] The major metabolites of parabens are p-hydroxybenzoic acid (pHBA), p-hydroxyhippuric acid (M1), p-hydroxybenzoyl glucuronide (M3), and p-carboxyphenylsulfate (M4).[10]

Allergic reactions

In individuals with normal skin, parabens are, for the most part, non-irritating and non-sensitizing. Parabens can, however, cause skin irritation and contact dermatitis and Rosacea in individuals with paraben allergies, a small percentage of the general population.[11]

Breast cancer

Several peer-reviewed studies have reported results that indirectly support a correlation between the presence of parabens and the occurrence of breast cancer. High levels of parabens have been detected in breast tumors,[12][2] with one UK-based study finding high concentrations of parabens in eighteen out of twenty samples of breast tumors.[2] These findings, along with the demonstrated ability of parabens to mimic estrogen, a hormone known to play a role in the development of breast cancers,[2] have led some scientists to conclude that the presence of parabens is associated with the occurrence of breast cancer,[7][13] and to call for investigation into whether or not a causal link exists.[14] The lead researcher of the UK study, molecular biologist Philippa Darbre, reported that the ester-bearing form of the parabens found in the tumors indicate that they came from something applied to the skin, such as an underarm deodorant, cream or body spray, and stated that the results helped to explain why up to 60% of all breast tumors are found in just one-fifth of the breast - the upper-outer quadrant, nearest the underarm.[7] "From this research it is not possible to say whether parabens actually caused these tumors, but they may certainly be associated with the overall rise in breast cancer cases. Given that breast cancer is a large killer of women and a very high percentage of young women use underarm deodorants, I think we should be carrying out properly funded, further investigations into parabens and where they are found in the body," says Philip Harvey, an editor of the Journal of Applied Toxicology, which published the research.[7] A 2004 study at Northwestern University found that an earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving.[15] "I personally feel there is a very strong correlation between the underarm hygiene habits and breast cancer," said immunologist Dr. Kris McGrath, the author of the study.[13]

This research has fueled a popular belief that the parabens in underarm deodorants and other cosmetics can migrate into breast tissue and contribute to the development of tumors.

No direct evidence of a causal link between parabens and cancer, however, has been shown. A 2005 review of the data available at that time concluded "it is biologically implausible that parabens could increase the risk of any estrogen-mediated endpoint, including effects on the male reproductive tract or breast cancer" and that "worst-case daily exposure to parabens would present substantially less risk relative to exposure to naturally occurring endocrine active chemicals in the diet such as the phytoestrogen daidzein."[16] The American Cancer Society also concluded that there was insufficient scientific evidence to support a claim that use of cosmetics such as antiperspirants increase an individual's risk of developing breast cancer, but went on to state that "larger studies are needed to find out what effect, if any, parabens might have on breast cancer risk.[17]

While current studies do not causally link parabens with tumors, neither do these studies demonstrate that parabens are safe; the long-term health effects of exposure to parabens are essentially unknown.[18]

A further systematic review in 2008 examined 59 earlier publications (19 in depth) for answers to the questions:

  1. Are there experimental or biological arguments supporting a potential link between the use of deodorants/antiperspirants and breast cancer?
  2. Does the use of deodorants/antiperspirants have any effect on the increase in the risk of breast cancer?
  3. Could a causal relationship between the use of deodorants/antiperspirants and breast cancer be accepted?

They found "no scientific evidence to support the hypothesis was identified and no validated hypothesis appears likely to open the way to interesting avenues of research." They conclude "Au final, il semble possible d’affirmer que cette question ne constitue pas un problème de santé publique et qu’il apparaît donc inutile de poursuivre les recherches sur ce sujet." (Finally, it seems possible to affirm that this question does not constitute a problem of public health and that it appears therefore useless to pursue the research on the subject.) [19]

Estrogenic activity

Animal experiments have shown that parabens have weak estrogenic activity, acting as xenoestrogens.[20] In an in vivo study, the effect of butylparaben was determined to be approximately 100,000 times weaker than that of estradiol, and was only observed at a dose level approximately 25,000 times higher than the level typically used to preserve products.[21] The study also found that the in vivo estrogenic activity of parabens is reduced by about three orders of magnitude compared to in vitro activity.

The estrogenic activity of parabens increases with the length of the alkyl group. It is believed that propylparaben is estrogenic to a certain degree as well,[22] though this is expected to be less than butylparaben by virtue of its less lipophilic nature. Since it can be concluded that the estrogenic activity of butylparaben is negligible under normal use, the same should be concluded for shorter analogs.

Some estrogens are known to drive the growth of tumors; however the estrogenic activity and mutagenic activity of estrogens are not the same, with the latter dependent on free radical chemistry and not estrogen receptor activity.[23] Nonetheless, this study has elicited some concern about the use of butylparaben, and to a lesser extent other parabens as well, in cosmetics and antiperspirants. A 2005 safety assessment of parabens concluded that cosmetics containing parabens do not, on the basis of currently available evidence, pose a health risk; because of the low doses involved and the low probability that parabens will penetrate into the tissue, remain intact, and accumulate there.[8]

Sun exposure

Studies indicate that methylparaben applied on the skin may react with UVB leading to increased skin aging and DNA damage.[24][25]

Regulation

Nevertheless, the European Scientific Committee on Consumer Products (SCCP) stated in 2006 that the available data on parabens do not enable a decisive response to the question of whether propyl, butyl and isobutyl paraben can be safely used in cosmetic products at individual concentrations up to 0.4%, which is the allowed limit in the EU.[26]

Controversy

The above-mentioned studies have resulted in scientific debate that in turn led to popular controversy largely propagated by mass e-mail. [27][28] Darbre's paper led to some concerns over possible carcinogenicity[29] or estrogenic effects being expressed[citation needed] over the continued use of parabens as preservatives.

The mainstream cosmetic industry believes that parabens, like most cosmetic ingredients, are safe based on their long term use and safety record and recent scientific studies.[30] Public interest organizations which raise awareness about cosmetic ingredients believe that further research is necessary to determine the safety of parabens (see also precautionary principle).[29] The concerns about endocrine disruptors have led consumers and companies to search for paraben free alternatives.[31] Grapefruit seed extract that is promoted as a natural preservative was identified as containing artificial preservatives such as methylparaben.[1]

See also

References

  1. ^ a b von Woedtke T, Schluter B, Pflegel P, Lindequist U, Julich WD (1999 June). "Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained". Pharmazie. 54 (6). Greifswald, Germany: Institute of Pharmacy, Ernst Moritz Arndt University,: 452–6. PMID 10399191. {{cite journal}}: Check date values in: |date= (help)CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  2. ^ a b c d e Harvey PW, Everett DJ (2004). "Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours". Journal of Applied Toxicology. 24 (1): 1–4. doi:10.1002/jat.957. PMID 14745840. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ Golden R, Gandy J, Vollmer G (2005). "A review of the endocrine activity of parabens and implications for potential risks to human health". Critical Reviews in Toxicology. 35 (5): 435–58. doi:10.1080/10408440490920104. PMID 16097138.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Al-Shamma A, Drake S, Flynn DL, Mitscher LA, Park YH, Rao GSR, Simpson A, Swayze JK, Veysoglu T, Wu STS (1981). "Antimicrobial Agents From Higher Plants. Antimicrobial Agents From Peganum harmala Seeds". J Nat Prod. 44 (6): 745–747. doi:10.1021/np50018a025. PMID 7334386.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Bais HP, Vepachedu R, Vivanco JM, (1 April 2003). "Root specific elicitation and exudation of fluorescent beta-carbolines in transformed root cultures of Oxalis tuberosa". Plant Physiology and Biochemistry. 41 (4): 345–353. doi:10.1016/S0981-9428(03)00029-9.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  6. ^ "In Vitro Cellular and Developmental Biology". Plant. 37 (6): 730–741. 2001.
  7. ^ a b c d Vince G (12 January 2004). "Cosmetic chemicals found in breast tumours". New Scientist.
  8. ^ a b c Soni MG, Carabin IG, Burdock GA (2005). "Safety assessment of esters of p-hydroxybenzoic acid (parabens)". Food and Chemical Toxicology. 43 (7): 985–1015. doi:10.1016/j.fct.2005.01.020. PMID 15833376.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Soni MG, Taylor SL, Greenberg NA, Burdock GA (2002). "Evaluation of the health aspects of methyl paraben: a review of the published literature". Food and Chemical Toxicology. 40 (10): 1335–73. doi:10.1016/S0278-6915(02)00107-2. PMID 12387298.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Elder RL (1984). "Final report on the safety assessment of methylparaben, ethylparaben, propylparaben, and butylparaben". J Am Coll Toxicol. 3: 147–209.
  11. ^ Nagel JE, Fuscaldo JT, Fireman P. Paraben allergy (April 11, 1977). "Paraben allergy". J Am Med Assoc. 237 (15): 1594–5. doi:10.1001/jama.237.15.1594. PMID 576658.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS (2004 Jan-Feb). "Concentrations of parabens in human breast tumours". J Appl Toxicol. 24 (1): 5–13. doi:10.1002/jat.958. PMID 14745841. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)
  13. ^ a b Lagorio, Christine (Dec. 5, 2005). "The Cancer-Antiperspirant "Myth": Could Shaving And Antiperspirant Be Related To Breast Cancer?". CBS News. Retrieved 2 Jan 2009. {{cite news}}: Check date values in: |date= (help)
  14. ^ Harvey PW, Darbre P (2004). "Endocrine disruptors and human health: Could estrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women? A review of evidence and call for further research". Journal of Applied Toxicology. 24 (3): 167–76. doi:10.1002/jat.978. PMID 15211609.
  15. ^ McGrath, Kris (2003 Dec). "An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving". European Journal of Cancer Prevention. 12 (6): 479–85. doi:10.1097/00008469-200312000-00006. PMID 14639125. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Golden R, Gandy J, Vollmer G (2005). "A review of the endocrine activity of parabens and implications for potential risks to human health". Critical Reviews in Toxicology. 35 (5): 435–58. doi:10.1080/10408440490920104. PMID 16097138.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ The American Cancer Society Antiperspirants and Breast Cancer Risk
  18. ^ "Antiperspirant chemical found in breast tumours". Web MD.
  19. ^ Namer M, Luporsi E, Gligorov J, Lokiec F, Spielmann M (2008 Sep). "[The use of deodorants/antiperspirants does not constitute a risk factor for breast cancer]". Bulletin du Cancer (in French with English abstract). 95 (9): 871–80. doi:10.1684/bdc.2008.0679. PMID 18829420. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |doi_brokendate= ignored (|doi-broken-date= suggested) (help)CS1 maint: multiple names: authors list (link) CS1 maint: unrecognized language (link)
  20. ^ Byford JR, Shaw LE, Drew MG, Pope GS, Sauer MJ, Darbre PD (2002 Jan). "Oestrogenic activity of parabens in MCF7 human breast cancer cells". J Steroid Biochem Mol Biol. 80 (1): 49–60. doi:10.1016/S0960-0760(01)00174-1. PMID 11867263. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)
  21. ^ Edwin J. Routledge; et al. (1998). "Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic". Toxicology and Applied Pharmacology. 153 (1): 12–19. doi:10.1006/taap.1998.8544. PMID 9875295. {{cite journal}}: Explicit use of et al. in: |author= (help)
  22. ^ Cashman AL, Warshaw EM (2005 Jun). "Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties". Dermatitis. 16 (2): 57–66. PMID 16036114. {{cite journal}}: Check date values in: |date= (help); More than one of |at= and |pages= specified (help)
  23. ^ Fernandez SV, Russo IH, Russo J (2006-04-15). "Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells". Int J Cancer. 118 (8): 1862–8. doi:10.1002/ijc.21590. PMID 16287077.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Osamu Handa, Satoko Adachi, Tomohisa Takagi; et al. (3 October 2006). "Methylparaben potentiates UV-induced damage of skin keratinocytes". Toxicology. 227 (1–2): 62–72. doi:10.1016/j.tox.2006.07.018. PMID 16938376. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  25. ^ Yoshinori Okamoto, Tomohiro Hayashi, Shinpei Matsunami, Koji Ueda, Nakao Kojima (July 26, 2008). "Combined activation of methyl paraben by light irradiation and esterase metabolism toward oxidative DNA damage". Chemical Research in Toxicology. 21 (8): 1594–9. doi:10.1021/tx800066u. PMID 18656963.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ SCCP: Opinion on Parabens. Colipa No P82 10 Oct 2006.
  27. ^ Jones J (September 20, 2000). "Can rumors cause cancer?". Journal of the National Cancer Institute. 92 (18): 1469–71. doi:10.1093/jnci/92.18.1469.
  28. ^ "Antiperspirants do NOT cause breast cancer". Breastcancer.org. August 15, 2008. Retrieved April 15, 2010.
  29. ^ a b Rita Arditti (June 9, 2004). "Cosmetics, parabens, and breast cancer". Organic Consumers Association.
  30. ^ "The truth about antiperspirants and breast cancer". Unilever.
  31. ^ Lebovits SC (May 26, 2008). "Cosmetics firms heed calls for organics". The Boston Globe.
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